Mencacci Niccolo E, Rubio-Agusti Ignacio, Zdebik Anselm, Asmus Friedrich, Ludtmann Marthe H R, Ryten Mina, Plagnol Vincent, Hauser Ann-Kathrin, Bandres-Ciga Sara, Bettencourt Conceição, Forabosco Paola, Hughes Deborah, Soutar Marc M P, Peall Kathryn, Morris Huw R, Trabzuni Daniah, Tekman Mehmet, Stanescu Horia C, Kleta Robert, Carecchio Miryam, Zorzi Giovanna, Nardocci Nardo, Garavaglia Barbara, Lohmann Ebba, Weissbach Anne, Klein Christine, Hardy John, Pittman Alan M, Foltynie Thomas, Abramov Andrey Y, Gasser Thomas, Bhatia Kailash P, Wood Nicholas W
Department of Molecular Neuroscience, Institute of Neurology, University College London, WC1N 3BG London, UK; IRCCS Istituto Auxologico Italiano, Department of Neurology and Laboratory of Neuroscience, Department of Pathophysiology and Transplantation, "Dino Ferrari" Centre, Universita degli Studi di Milano, 20149 Milan, Italy.
Unidad de Trastornos del Movimiento, Hospital Universitario La Fe, 46026 Valencia, Spain; Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, WC1N 3BG London, UK.
Am J Hum Genet. 2015 Jun 4;96(6):938-47. doi: 10.1016/j.ajhg.2015.04.008. Epub 2015 May 14.
Myoclonus-dystonia (M-D) is a rare movement disorder characterized by a combination of non-epileptic myoclonic jerks and dystonia. SGCE mutations represent a major cause for familial M-D being responsible for 30%-50% of cases. After excluding SGCE mutations, we identified through a combination of linkage analysis and whole-exome sequencing KCTD17 c.434 G>A p.(Arg145His) as the only segregating variant in a dominant British pedigree with seven subjects affected by M-D. A subsequent screening in a cohort of M-D cases without mutations in SGCE revealed the same KCTD17 variant in a German family. The clinical presentation of the KCTD17-mutated cases was distinct from the phenotype usually observed in M-D due to SGCE mutations. All cases initially presented with mild myoclonus affecting the upper limbs. Dystonia showed a progressive course, with increasing severity of symptoms and spreading from the cranio-cervical region to other sites. KCTD17 is abundantly expressed in all brain regions with the highest expression in the putamen. Weighted gene co-expression network analysis, based on mRNA expression profile of brain samples from neuropathologically healthy individuals, showed that KCTD17 is part of a putamen gene network, which is significantly enriched for dystonia genes. Functional annotation of the network showed an over-representation of genes involved in post-synaptic dopaminergic transmission. Functional studies in mutation bearing fibroblasts demonstrated abnormalities in endoplasmic reticulum-dependent calcium signaling. In conclusion, we demonstrate that the KCTD17 c.434 G>A p.(Arg145His) mutation causes autosomal dominant M-D. Further functional studies are warranted to further characterize the nature of KCTD17 contribution to the molecular pathogenesis of M-D.
肌阵挛性肌张力障碍（M-D）是一种罕见的运动障碍，其特征为非癫痫性肌阵挛抽搐和肌张力障碍并存。SGCE突变是家族性M-D的主要病因，占病例的30%-50%。在排除SGCE突变后，我们通过连锁分析和全外显子测序相结合的方法，在一个有7名受试者患M-D的显性英国家系中，确定KCTD17基因c.434 G>A p.(Arg145His)为唯一的分离变异。随后在一组SGCE无突变的M-D病例中进行筛查，发现一个德国家庭中也存在相同的KCTD17变异。KCTD17突变病例的临床表现与通常在由SGCE突变引起的M-D中观察到的表型不同。所有病例最初均表现为影响上肢的轻度肌阵挛。肌张力障碍呈进行性发展，症状逐渐加重并从颅颈区域蔓延至其他部位。KCTD17在所有脑区均有丰富表达，在壳核中表达最高。基于神经病理学健康个体脑样本的mRNA表达谱进行的加权基因共表达网络分析表明，KCTD17是壳核基因网络的一部分，该网络中肌张力障碍相关基因显著富集。对该网络的功能注释显示，参与突触后多巴胺能传递的基因过度表达。对携带突变的成纤维细胞进行的功能研究表明，内质网依赖性钙信号存在异常。总之，我们证明KCTD17基因c.434 G>A p.(Arg145His)突变导致常染色体显性M-D。有必要进行进一步的功能研究，以进一步明确KCTD17在M-D分子发病机制中的作用性质。
